Clinical studies of patients with treatment-resistant depression have shown that combined treatment with fluoxetine and olanzapine rapidly and significantly improved depressive symptoms. The present study used in vivo microdialysis to investigate the brain regional and dose effects of these drugs on extracellular monoamine concentrations in the rat prefrontal cortex, hypothalamus, nucleus accumbens and striatum. In the prefrontal cortex, the olanzapine/fluoxetine combination (3/10 mg/kg, respectively) increased catecholamine concentrations to a significantly greater extent than either drug alone (dopamine mean+/-S.E.M. percent of baseline: olanzapine (120 +/- 12.4), fluoxetine (123 +/- 6.2), combination (185 +/- 8.8); norepinephrine: olanzapine (124 +/- 7.2), fluoxetine (126 +/- 5.0), combination (215 +/- 15.8)). The combination also increased serotonin concentrations to 156 +/- 11.0% of baseline, but to a lesser extent than fluoxetine alone (210 +/- 14.5%). Similar synergistic effects of the combination were observed in the hypothalamus, but not in the other regions studied. The dose response effects of the drugs alone and in combination were complex, but larger doses of the combinations produced greater monoamine concentration increases than smaller dose combinations. The effects of the olanzapine/fluoxetine combination are meaningful in prefrontal cortex and hypothalamus due to their hypothesized role in the etiology and pharmacotherapy of depression. The wide-ranging neurochemical effects of this drug combination may make it particularly useful as a treatment for complex, resistant depressions.